Mitogen-activated protein kinases (MAP) are a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation. The kinases are activated by a variety of signals including nutritional and osmotic stress, UV light, growth factors, endotoxin, and inflammatory cytokines. One group of MAP kinases is the p38 kinase group which includes various isoforms (e.g., p38α, p39β, p38γ and p38δ). The p38 kinases are responsible for phosphorylating and activating transcription factors (as well as other kinases), and are themselves activated by physical and chemical stress, pro-inflammatory cytokines, and bacterial lipopolysaccharide.
More importantly, the products of the p38 phosphorylation have been shown to mediate the production of inflammatory cytokines, including TNF, IL-1, IL-6, and cyclooxygenase-2 (COX-2). Each of these cytokines has been implicated in numerous disease states and conditions. For example, TNF-α is a cytokine produced primarily by activated monocytes and macrophages. Excessive or unregulated production of TNF-α has been implicated as playing a causative role in the pathogenesis of rheumatoid arthritis. More recently, inhibition of TNF production has been shown to have broad application in the treatment of inflammatory conditions, inflammatory bowel disease, Alzheimer's disease, Crohn's disease, multiple sclerosis, and asthma.
Additionally, TNF has been implicated in viral infections, such as HIV, influenza virus, and herpes virus including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpes virus-6 (HHV-6), human herpes virus-7 (HHV-7), human herpes virus-8 (HHV-8), pseudorabies, and rhinotracheitis, among others.
Similarly, IL-1 is produced by activated monocytes and macrophages and plays a role in many pathophysiological responses including rheumatoid arthritis, fever and reduction of bone resorption.
The inhibition of these cytokines by inhibition of the p38 kinase would be beneficial in controlling, reducing and alleviating many of these disease states. p38 MAP kinase inhibitors have demonstrated efficacy in several disease models including arthritis and other joint diseases, sepsis, stroke, myocardial injury, respiratory inflammatory diseases such as chronic obstructive pulmonary disease and asthma, and a wide range of inflammatory conditions. The present invention provides certain 2-amino-6-phenoxy substituted quinazoline compounds useful in inhibiting p38 kinase. U.S. patent application Ser. No. 10/824,731, filed concomitantly herewith and assigned to the present assignee, discloses 2-amino-6-phenoxy substituted quinazoline compounds useful as p38 kinase inhibitors, and the entire contents of said application is hereby incorporated herein by reference.